A Systematic Literature Review and Meta-Regression Analysis on Early-Life Energy Restriction and Cancer Risk in Humans.

BACKGROUND: In animal models, long-term moderate energy restriction (ER) is reported to decelerate carcinogenesis, whereas the effect of severe ER is inconsistent. The impact of early-life ER on cancer risk has never been reviewed systematically and quantitatively based on observational studies in humans. OBJECTIVE: We conducted a systematic review of observational studies and a meta-(regression) analysis on cohort studies to clarify the association between early-life ER and organ site-specific cancer risk. METHODS: PubMed and EMBASE (1982 -August 2015) were searched for observational studies. Summary relative risks (RRs) were estimated using a random effects model when available ≥3 studies. RESULTS: Twenty-four studies were included. Eleven publications, emanating from seven prospective cohort studies and some reporting on multiple cancer endpoints, met the inclusion criteria for quantitative analysis. Women exposed to early-life ER (ranging from 220-1660 kcal/day) had a higher breast cancer risk than those not exposed (RRRE all ages = 1.28, 95% CI: 1.05-1.56; RRRE for 10-20 years of age = 1.21, 95% CI: 1.09-1.34). Men exposed to early-life ER (ranging from 220-800kcal/day) had a higher prostate cancer risk than those not exposed (RRRE = 1.16, 95% CI: 1.03-1.30). Summary relative risks were not computed for colorectal cancer, because of heterogeneity, and for stomach-, pancreas-, ovarian-, and respiratory cancer because there were <3 available studies. Longer duration of exposure to ER, after adjustment for severity, was positively associated with overall cancer risk in women (p = 0.02). Ecological studies suggest that less severe ER is generally associated with a reduced risk of cancer. CONCLUSIONS: Early-life transient severe ER seems to be associated with increased cancer risk in the breast (particularly ER exposure at adolescent age) and prostate. The duration, rather than severity of exposure to ER, seems to positively influence relative risk estimates. This result should be interpreted with caution due to the limited number of studies and difficulty in disentangling duration, severity, and geographical setting of exposure.

Oxidative stress-related genetic variants, pro- and antioxidant intake and status, and advanced prostate cancer risk.

BACKGROUND: Increased oxidative stress has been linked to prostate cancer. We investigated oxidative stress-related genetic variants in relation to advanced prostate cancer risk and examined potential interactions with pro- and antioxidant exposures. METHODS: A case-cohort analysis was conducted in the prospective Netherlands Cohort Study, which included 58,279 men ages 55 to 69 years. Cohort members completed a baseline questionnaire and provided toenail clippings, which were used to isolate DNA. Advanced prostate cancer cases were identified during 17.3 years of follow-up. The analysis included 14 genetic variants and 11 exposures. Cox regression models were used for analysis and FDR Q-values were calculated. RESULTS: Complete genotyping data were available for 952 cases and 1,798 subcohort members. CAT rs1001179 was associated with stage III/IV and stage IV prostate cancer risk, with HRs per minor allele of 1.16 [95% confidence intervals (CI), 1.01-1.33; P = 0.032] and 1.25 (95% CI, 1.07-1.46; P = 0.006), respectively. We tested 151 gene-environment interactions in relation to both stage III/IV and IV prostate cancer risk. Seven interactions were statistically significant after adjusting for multiple testing (FDR Q-value <0.20); for stage III/IV prostate cancer, these involved intake of ß-carotene (GPX1 rs17650792, hOGG1 rs1052133) and heme iron (GPX1 rs1800668 and rs3448), and for stage IV prostate cancer, these involved intake of catechin (SOD2 rs4880) and heme iron (hOGG1 rs1052133, SOD1 rs10432782). CONCLUSION: This study of advanced prostate cancer risk showed a marginal association with a CAT polymorphism and seven novel gene-environment interactions in the oxidative stress pathway. IMPACT: Oxidative stress-related genes and exposures may have a joint effect on advanced prostate cancer. Cancer Epidemiol Biomarkers Prev; 24(1); 178-86. ©2014 AACR.

DNA from nails for genetic analyses in large-scale epidemiologic studies.

BACKGROUND: Nails contain genomic DNA that can be used for genetic analyses, which is attractive for large epidemiologic studies that have collected or are planning to collect nail clippings. Study participants will more readily participate in a study when asked to provide nail samples than when asked to provide a blood sample. In addition, nails are easy and cheap to obtain and store compared with other tissues. METHODS: We describe our findings on toenail DNA in terms of yield, quality, genotyping a limited set of SNPs with the Sequenom MassARRAY iPLEX platform and high-density genotyping with the Illumina HumanCytoSNP_FFPE-12 DNA array (>262,000 markers). We discuss our findings together with other studies on nail DNA and we compare nails and other frequently used tissue samples as DNA sources. RESULTS: Although nail DNA is considerably degraded, genotyping a limited set of SNPs with the Sequenom MassARRAY iPLEX platform (average sample call rate, 97.1%) and high-density genotyping with the Illumina HumanCytoSNP_FFPE chip (average sample call rate, 93.8%) were successful. CONCLUSIONS: Nails are a suitable source of DNA for genotyping in large-scale epidemiologic studies, provided that methods are used that are suitable or optimized for degraded DNA. For genotyping through (next generation) sequencing where DNA degradation is less of an issue, nails may be an even more attractive DNA source, because it surpasses other sources in terms of ease and costs of obtaining and storing the samples. IMPACT: It is worthwhile to consider nails as a source of DNA for genotyping in large-scale epidemiologic studies. See all the articles in this CEBP Focus section, "Biomarkers, Biospecimens, and New Technologies in Molecular Epidemiology." Cancer Epidemiol Biomarkers Prev; 23(12); 2703-12. ©2014 AACR.

Dietary one-carbon nutrient intake and risk of lymphoid and myeloid neoplasms: results of the Netherlands cohort study.

BACKGROUND: Previous epidemiologic research suggests a protective role of one-carbon nutrients in carcinogenesis. Folate, however, may play a dual role in neoplasms development: protect early in carcinogenesis and promote carcinogenesis at a later stage. We prospectively examined associations between intake of total folate, methionine, riboflavin, vitamin B6, and risk of lymphoid and myeloid neoplasms (including subtypes) and investigated whether alcohol modified the effects of folate. METHODS: The Netherlands Cohort Study consists of 120,852 individuals who completed a baseline questionnaire in 1986, including a 150-item food-frequency questionnaire. After 17.3 years of follow-up, 1,280 cases of lymphoid and 222 cases of myeloid neoplasms were available for analysis. RESULTS: Intakes of folate, methionine, and riboflavin were not associated with lymphoid or myeloid neoplasms. For vitamin B6, a statistically significantly increased myeloid neoplasms risk was observed (highest vs. lowest quintile: HR = 1.87; 95% confidence intervals, 1.08-3.25). When analyzing by lymphoid and myeloid neoplasms subtypes, no clear associations were observed for most subtypes, with just a few increased risks for some subtypes and nutrients. Some risks became nonsignificant after excluding early cases. No interaction between alcohol and folate was observed. CONCLUSIONS: We observed a few significant positive associations; however, some of these would be expected to arise due to chance alone. Furthermore, some risks became nonsignificant after excluding early cases. Therefore, we conclude that there is no association between one-carbon nutrient intake and risk of lymphoid and myeloid neoplasms. IMPACT: This study contributes substantially to the limited and inconclusive evidence on the association with one-carbon nutrients.

Selenoprotein gene variants, toenail selenium levels, and risk for advanced prostate cancer.

Lower selenium levels have been associated with increased risk of prostate cancer (PCa), and genetic variation in the selenoprotein genes selenoprotein P (SEPP1) and glutathione peroxidase 1 (GPX1) is thought to modify this relationship. We investigated whether the association between toenail selenium levels and advanced PCa risk in the prospective Netherlands Cohort Study is modified by common genetic variation in SEPP1 and GPX1. Toenail clippings were used to determine selenium levels and to isolate DNA for genotyping. This case-cohort study, which included 817 case subjects with advanced PCa and 1048 subcohort members, was analyzed with Cox regression models. All statistical tests were two-sided. Three genetic variants were associated with advanced (stage III/IV or IV) PCa risk: SEPP1 rs7579 (lower risk; P trend = .01), GPX1 rs17650792 (higher risk; P trend = .03), and GPX1 rs1800668 (lower risk; P trend = .005). Toenail selenium levels were inversely associated with advanced PCa risk, independently of common genetic variation in SEPP1 and GPX1.

Advanced prostate cancer risk in relation to toenail selenium levels.

BACKGROUND: Selenium may prevent advanced prostate cancer (PCa), but most studies on this topic were conducted in populations with moderate to high selenium status. We investigated the association of toenail selenium, reflecting long-term selenium exposure, and advanced PCa risk in a population from the Netherlands where low selenium status is widespread. METHODS: The analysis was conducted in the prospective Netherlands Cohort Study, which included 58 279 men aged 55 to 69 years at baseline in 1986. All cohort members completed a baseline questionnaire, and approximately 79% of participants provided toenail clippings, which were used for toenail selenium measurements using instrumental neutron activation analysis. Incident advanced PCa case subjects from the entire cohort were identified during 17.3 years of follow-up. The study employed a case-cohort design for which a random subcohort was sampled at baseline. Hazard ratios and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression models. All tests were two-sided. RESULTS: Complete toenail selenium data were available for 898 advanced (International Union Against Cancer stage III/IV) PCa case subjects and 1176 subcohort members. The average toenail selenium concentration of subcohort members was 0.550 µg/g. Toenail selenium was associated with a reduced risk of advanced PCa; adjusted hazard ratio for the highest vs lowest quintile was 0.37 (95% CI = 0.27 to 0.51; P trend < .001). For stage IV PCa, men in the highest vs lowest quintile of toenail selenium had an adjusted hazard ratio of 0.30 (95% CI = 0.21 to 0.45; P trend < .001). CONCLUSIONS: Toenail selenium was associated with a substantial decrease in risk of advanced PCa.

Dietary flavonoid intake, black tea consumption, and risk of overall and advanced stage prostate cancer.

Flavonoids are natural antioxidants found in various foods, and a major source is black tea. Some experimental evidence indicates that flavonoids could prevent prostate cancer. We investigated the associations between flavonoid intake, black tea consumption, and prostate cancer risk in the Netherlands Cohort study, which includes 58,279 men who provided detailed baseline information on several cancer risk factors. From 1986 to 2003, 3,362 prostate cancers were identified, including 1,164 advanced (stage III/IV) cancers. Cox proportional hazards regression using the case-cohort approach was used to estimate hazard ratios and 95% confidence intervals. Intake of total catechin, epicatechin, kaempferol, and myricetin and consumption of black tea were associated with a decreased risk of stage III/IV or stage IV prostate cancer. Hazard ratios of stage III/IV and stage IV prostate cancer for the highest versus the lowest category of black tea consumption (≥5 versus ≤1 cups/day) were 0.75 (95% confidence interval: 0.59, 0.97) and 0.67 (95% confidence interval: 0.50, 0.91), respectively. No associations were observed for overall and nonadvanced prostate cancer. In conclusion, dietary flavonoid intake and black tea consumption were associated with a decreased risk of advanced stage prostate cancer.

Alcohol consumption and risk of lymphoid and myeloid neoplasms: results of the Netherlands cohort study.

Results from epidemiological studies suggest that alcohol drinkers have a decreased risk of lymphoid neoplasms, whereas results for myeloid neoplasms are inconsistent. However, most of these studies have used retrospective data. We examined prospectively whether alcohol consumption decreases the risk of both lymphoid and myeloid neoplasms, including most common subtypes. Moreover, we investigated whether this decreased risk is due to ethanol or other contents of specific alcoholic beverages (i.e., beer, wine and liquor). The Netherlands cohort study consisted of 120,852 individuals who completed a baseline questionnaire in 1986. After 17.3 years of follow-up, 1,375 cases of lymphoid and 245 cases of myeloid neoplasms with complete exposure information were available for analysis. Compared with abstinence, we observed for plasma cell neoplasms hazard rate ratios (HR) of 1.66 (95% confidence interval (CI), 1.21-2.29), 1.63 (95% CI, 1.17-2.27), 1.11 (95% CI, 0.75-1.64) and 0.85 (95% CI, 0.51-1.42) with daily ethanol consumption of 0.1-<5, 5-<15, 15-<30 and ≥30 g, respectively. A similar pattern was observed for chronic lymphocytic leukemia/small lymphocytic lymphoma. No associations were observed for other subtypes and for myeloid neoplasms. When results were analyzed by beverage type, no clear associations were observed. In conclusion, our study did not show an inverse association between alcohol consumption and lymphoid neoplasms. Also, no inverse association was observed with myeloid neoplasms. If any association between alcohol consumption and lymphoid neoplasms exists, our study suggests an increased risk rather than a decreased risk.

Dietary folate and folate vitamers and the risk of prostate cancer in The Netherlands Cohort Study.

PURPOSE: The aim of the present study was to examine the association between intake of folate, and specific folate vitamers, and the risk of advanced and total prostate cancer. METHODS: The association between dietary folate and prostate cancer risk was evaluated in The Netherlands Cohort Study (NLCS) on diet and cancer, conducted among 58,279 men ages 55-69 years at baseline. Information on diet was collected at baseline by means of food frequency questionnaires. Incident cases were identified by record linkage with regional cancer registries and the Dutch National Database of Pathology Reports. After 17.3 years of follow-up, 3,669 incident prostate cancer cases, of which 1,290 advanced cases, and 2,336 male subcohort members were available for case-cohort analyses. RESULTS: Dietary folate was not associated with prostate cancer risk, nor with the risk of advanced prostate cancer, among men in the NLCS cohort (HR = 1.05, 95 % CI: 0.87-1.26 and HR = 1.09, 95 % CI: 0.88-1.35, respectively, for the highest quintile of folate intake vs. the lowest quintile). Specific folate vitamers were neither associated with the risk of prostate cancer or risk of advanced prostate cancer. CONCLUSIONS: Our results do not support an association of dietary folate or specific folate vitamers on the risk of prostate cancer, or advanced prostate cancer.

Measures of combined antioxidant and pro-oxidant exposures and risk of overall and advanced stage prostate cancer.

PURPOSE: Oxidative stress is possibly related to prostate carcinogenesis. We constructed a dietary antioxidant score, which is a measure of combined antioxidant exposures, and an oxidative balance score (OBS), which is a measure of combined antioxidant and pro-oxidant exposures. We hypothesized that both scores are inversely associated with the risk of prostate cancer (PCa). METHODS: We conducted a case-cohort study among 58,279 men in the Netherlands Cohort Study. Cohort members completed a baseline questionnaire. From 1986 to 2003, 3451 patients with PCa were identified including 1196 advanced cancers (stage III/IV). The antioxidant score and the OBS were created by summing quartile and category scores of individual score constituents, which had an equal weight. Pro-oxidants were scored in the opposite way to antioxidants. RESULTS: Both the antioxidant score and OBS were not associated with risk of overall PCa or PCa subgroups on the basis of disease stage. Most score constituents were not associated with the risk of PCa. Total catechin intake was associated with a decreased risk of stage IV PCa (greatest vs. lowest quartile: hazard ratio, 0.76; 95% confidence interval, 0.59-0.98). CONCLUSIONS: The antioxidant score and OBS were not associated with risk of overall and advanced-stage PCa.

Intake of vegetables, fruits, carotenoids and vitamins C and E and pancreatic cancer risk in The Netherlands Cohort Study.

Epidemiological data investigating the relation between fruit and vegetable consumption and pancreatic cancer risk have shown inconsistent results so far. Most case-control studies observed an inverse association with total fruit and vegetable consumption, whereas results from most cohort studies have largely been null. We examined prospectively the relation between pancreatic cancer risk and intake of vegetables, fruits, carotenoids and vitamins C and E. The Netherlands Cohort Study consisted of 120,852 men and women who completed a questionnaire at baseline in 1986, including a validated 150-item food-frequency questionnaire. After 16.3 years of follow-up, 423 cases were available for analysis. Total vegetable and total fruit consumption were not associated with pancreatic cancer risk (highest vs. lowest quintile, multivariable-adjusted hazard rate ratio = 1.23, 95% confidence interval: 0.86-1.75 and multivariable-adjusted hazard rate ratio = 0.90, 95% confidence interval: 0.66-1.24, respectively). Also, for cooked vegetables, raw vegetables and vegetables and fruits classified into subgroups, no associations were observed. Dietary carotenoids, vitamin C and E intake and supplements containing vitamin C or E were not associated with pancreatic cancer risk. The results were not modified by sex, smoking status and body mass index. In conclusion, we observed no association between a high consumption of vegetables and fruits and pancreatic cancer risk in this large cohort study, which is in agreement with previous prospective studies. Furthermore, we observed no association between the intake of carotenoids, vitamins and vitamin supplements and pancreatic cancer risk.

Physical activity, energy restriction, and the risk of pancreatic cancer: a prospective study in the Netherlands.

BACKGROUND: Because of their influence on insulin concentrations, we hypothesized that both physical activity and energy restriction may reduce the risk of pancreatic cancer. OBJECTIVE: We examined the associations between physical activity, proxies for energy restriction, and pancreatic cancer risk. DESIGN: The Netherlands Cohort Study consisted of 120,852 individuals who completed a baseline questionnaire in 1986. After 13.3 y of follow-up, 408 cases were available for analysis. Self-reported information on physical activity was collected. Three indicators were used as proxies for energy restriction: father's employment status during the Economic Depression (1932-1940) and place of residence during the World War II years (1940-1944) and the Hunger winter (1944-1945). RESULTS: For past sports activities, we observed a significantly decreased risk of pancreatic cancer (HR: 0.80; 95% CI: 0.64, 0.99). Proxies for energy restriction were not related to pancreatic cancer risk. When the results for energy restriction were stratified by height, a significant multiplicative interaction was observed for the Economic Depression period (P = 0.002). Shorter individuals (height less than the sex-specific median adult height) with an unemployed father during the Economic Depression period had a significantly lower cancer risk (HR: 0.31; 95% CI: 0.14, 0.66) than did taller individuals with an employed father. No significant interactions were observed for exposure to energy restriction during the World War II years and the Hunger winter. CONCLUSIONS: Our results suggest a modestly decreased risk of pancreatic cancer associated with past sports activity. With respect to proxies for energy restriction, our findings suggest that shorter individuals exposed to energy restriction during adolescence may have a reduced risk, whereas taller individuals may not.

A pooled analysis of 14 cohort studies of anthropometric factors and pancreatic cancer risk.

Epidemiologic studies of pancreatic cancer risk have reported null or nonsignificant positive associations for obesity, while associations for height have been null. Waist and hip circumference have been evaluated infrequently. A pooled analysis of 14 cohort studies on 846,340 individuals was conducted; 2,135 individuals were diagnosed with pancreatic cancer during follow-up. Study-specific relative risks (RRs) and 95% confidence intervals (CIs) were calculated by Cox proportional hazards models, and then pooled using a random effects model. Compared to individuals with a body mass index (BMI) at baseline between 21-22.9 kg/m(2) , pancreatic cancer risk was 47% higher (95%CI:23-75%) among obese (BMI ≥ 30 kg/m(2) ) individuals. A positive association was observed for BMI in early adulthood (pooled multivariate [MV]RR = 1.30, 95%CI = 1.09-1.56 comparing BMI ≥ 25 kg/m(2) to a BMI between 21 and 22.9 kg/m(2) ). Compared to individuals who were not overweight in early adulthood (BMI < 25 kg/m(2) ) and not obese at baseline (BMI < 30 kg/m(2) ), pancreatic cancer risk was 54% higher (95%CI = 24-93%) for those who were overweight in early adulthood and obese at baseline. We observed a 40% higher risk among individuals who had gained BMI ≥ 10 kg/m(2) between BMI at baseline and younger ages compared to individuals whose BMI remained stable. Results were either similar or slightly stronger among never smokers. A positive association was observed between waist to hip ratio (WHR) and pancreatic cancer risk (pooled MVRR = 1.35 comparing the highest versus lowest quartile, 95%CI = 1.03-1.78). BMI and WHR were positively associated with pancreatic cancer risk. Maintaining normal body weight may offer a feasible approach to reducing morbidity and mortality from pancreatic cancer.

Active and passive smoking and the risk of pancreatic cancer in the Netherlands Cohort Study.

BACKGROUND: To date, cigarette smoking is the most consistent risk factor for pancreatic cancer. We prospectively examined the role of active cigarette smoking, smoking cessation, and passive smoking as determinants for pancreatic cancer. METHODS: The Netherlands Cohort Study consisted of 120,852 men and women who completed a baseline questionnaire in 1986. After 16.3 years of follow-up, 520 incident pancreatic cancer cases were available for analysis. A case-cohort approach was employed using the person-years of follow-up of a random subcohort (n = 5,000), which was chosen immediately after baseline. RESULTS: Compared with never cigarette smokers, both former and current cigarette smokers had an increased pancreatic cancer risk [multivariable-adjusted hazard rate ratio (HR), 1.34; 95% confidence interval (CI), 1.02-1.75 and HR, 1.82; 95% CI, 1.40-2.38, respectively]. We observed an increased pancreatic cancer risk per increment of 10 years of smoking (HR, 1.15; 95% CI, 1.08-1.22) and an HR of 1.08 per increment of 10 cigarettes/d (95% CI, 0.98-1.19). Quitting smoking gradually reduced pancreatic cancer risk and approached unity after > or = 20 years of quitting. No association was observed for passive smoking exposure and pancreatic cancer risk in women; in men, this association was not investigated because >90% of the men were ever smokers. CONCLUSIONS: Overall, our findings confirmed that cigarette smoking is an important risk factor for pancreatic cancer, whereas quitting smoking reduced risk. No association was observed between passive smoking exposure and pancreatic cancer risk in women. IMPACT: Quitting smoking would benefit the burden on pancreatic cancer incidence.

Dietary folate and folate vitamers and the risk of pancreatic cancer in the Netherlands cohort study.

An association between high intake of folate and reduced risk of cancer has been suggested by previous research. However, epidemiologic data from cohort studies regarding the relationship between dietary folate and pancreatic cancer are sparse and inconsistent. We examined the association between dietary folate intake and risk of pancreatic cancer within the Netherlands Cohort Study on diet and cancer. Men and women (120,852), ages 55 to 69 years, were recruited. Information on diet was collected at baseline by means of food frequency questionnaires, and the cohort was followed for 13.3 years. Total folate and vitamer intake were calculated using folate contents of food items derived from a validated liquid chromatography trienzyme method. Cases (n = 363) were identified by record linkage with regional cancer registries and the Dutch National Database of Pathology Reports. A case-cohort approach was used using the follow-up data of a random subcohort (n = 5,000) identified at the onset of the cohort. Multivariable hazard ratios with 95% confidence intervals were estimated using Cox proportional hazards model. After adjusting for age, gender, smoking status, number of years smoked, number of cigarettes smoked per day, and intake of added sugar multivariate hazard ratio comparing the highest and lowest quintiles of folate intake for pancreatic cancer risk was 1.37 (confidence interval, 0.97-1.94; P(trend) = 0.07). When folate vitamers were analyzed separately, results did not show a difference in association. Our results do not support a protective association of total dietary folate or individual folate vitamers on the risk of pancreatic cancer.

Meat and fat intake and pancreatic cancer risk in the Netherlands Cohort Study.

Meat contains numerous carcinogens, such as heterocyclic amines, polycyclic aromatic hydrocarbons, and N-nitroso compounds, which can be derived either from natural food or during the process of food preparation. These carcinogens may increase pancreatic cancer risk. Furthermore, studies in animals showed that polyunsaturated fatty acids, especially linoleic acid, increase pancreatic cancer risk. We examined prospectively the relation between pancreatic cancer risk and intake of fresh meat, processed meat, fish, eggs, total fat, and different types of fat. The Netherlands Cohort Study consisted of 120,852 men and women who completed a baseline questionnaire in 1986. After 13.3 years of follow-up, 350 pancreatic cancer cases (66% microscopically confirmed) were available for analysis. A validated 150-item food-frequency questionnaire was used to calculate intake of fresh meat, processed meat, fish, eggs, fat and different types of fat. No association was found when examining the association between intake of fresh meat, other types of meat, fish, eggs, dietary intake of total fat and different types of fat and risk of pancreatic cancer. It is important for future studies to investigate the relation between different meat-cooking methods and pancreatic cancer.

Alcohol intake and pancreatic cancer risk: a pooled analysis of fourteen cohort studies.

BACKGROUND: Few risk factors have been implicated in pancreatic cancer etiology. Alcohol has been theorized to promote carcinogenesis. However, epidemiologic studies have reported inconsistent results relating alcohol intake to pancreatic cancer risk. METHODS: We conducted a pooled analysis of the primary data from 14 prospective cohort studies. The study sample consisted of 862,664 individuals among whom 2,187 incident pancreatic cancer cases were identified. Study-specific relative risks and 95% confidence intervals were calculated using Cox proportional hazards models and then pooled using a random effects model. RESULTS: A slight positive association with pancreatic cancer risk was observed for alcohol intake (pooled multivariate relative risk, 1.22; 95% confidence interval, 1.03-1.45 comparing >or=30 to 0 grams/day of alcohol; P value, test for between-studies heterogeneity=0.80). For this comparison, the positive association was only statistically significant among women although the difference in the results by gender was not statistically significant (P value, test for interaction=0.19). Slightly stronger results for alcohol intake were observed when we limited the analysis to cases with adenocarcinomas of the pancreas. No statistically significant associations were observed for alcohol from wine, beer, and spirits comparing intakes of >or=5 to 0 grams/day. A stronger positive association between alcohol consumption and pancreatic cancer risk was observed among normal weight individuals compared with overweight and obese individuals (P value, test for interaction=0.01). DISCUSSION: Our findings are consistent with a modest increase in risk of pancreatic cancer with consumption of 30 or more grams of alcohol per day.

Alcohol consumption and risk of pancreatic cancer in the Netherlands cohort study.

To examine prospectively the relation between alcohol consumption and pancreatic cancer risk, the authors analyzed data from the Netherlands Cohort Study. Participants were 120,852 persons who completed a baseline questionnaire in 1986. After 13.3 years of follow-up, 350 cases of pancreatic cancer (67% microscopically confirmed) were available for analysis. Compared with abstention, the highest category of alcohol consumption (> or =30 g/day of ethanol) was positively associated with pancreatic cancer risk (for all cases, rate ratio = 1.57, 95% confidence interval: 1.03, 2.39; P(trend) = 0.12; for microscopically confirmed cases, rate ratio = 1.54, 95% confidence interval: 0.94, 2.54; P(trend) = 0.22). In a subgroup of stable alcohol users (no change during the 5 years before baseline), a similarly increased risk of pancreatic cancer was found. This increased risk was limited to the first 7 years of follow-up. No associations were observed between consumption of specific alcoholic beverages and risk of pancreatic cancer. The associations were not modified by folate intake or smoking. Overall, these findings suggest an increased pancreatic cancer risk for persons with a high ethanol intake (> or =30 g/day). However, this increased risk was observed only during the first 7 years of follow-up.

Fruit and vegetable consumption and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition.

Many case-control studies have suggested that higher consumption of fruit and vegetables is associated with a lower risk of pancreatic cancer, whereas cohort studies do not support such an association. We examined the associations of the consumption of fruits and vegetables and their main subgroups with pancreatic cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC is comprised of over 520,000 subjects recruited from 10 European countries. The present study included 555 exocrine pancreatic cancer cases after an average follow-up of 8.9 years. Estimates of risk were obtained by Cox proportional hazard models, stratified by age at recruitment, gender, and study center, and adjusted for total energy intake, weight, height, history of diabetes mellitus, and smoking status. Total consumption of fruit and vegetables, combined or separately, as well as subgroups of vegetables and fruits were unrelated to risk of pancreatic cancer. Hazard ratios (95% CI) for the highest versus the lowest quartile were 0.92 (0.68-1.25) for total fruit and vegetables combined, 0.99 (0.73-1.33) for total vegetables, and 1.02 (0.77-1.36) for total fruits. Stratification by gender or smoking status, restriction to microscopically verified cases, and exclusion of the first 2 years of follow-up did not materially change the results. These results from a large European prospective cohort suggest that higher consumption of fruit and vegetables is not associated with decreased risk of pancreatic cancer.

Anthropometry and pancreatic cancer risk: an illustration of the importance of microscopic verification.

Using data collected of a large population-based cohort study, we studied the association between anthropometric factors and the risk of pancreatic cancer. Furthermore, we investigated whether these associations differ among microscopically confirmed pancreatic cancer (MCPC) cases and non-MCPC (NMCPC) cases. The Netherlands Cohort Study on Diet and Cancer started in 1986 (120,852 men and women) and uses the case-cohort methodology. After 13.3 years of follow-up, 446 pancreatic cancer cases (of which 65% was microscopically confirmed) and 4,774 subcohort members were available for analysis. The multivariable incidence rate ratio of MCPC of men was 1.10 per increment of 1 kg.m(-2) (95% confidence interval, 1.04-1.18). Women had a rate ratio of MCPC of 1.08 (95% confidence interval, 1.03-1.13). Obese men [body mass index (BMI) >or=30 kg.m(-2)] had a 2.6-fold increased risk of MCPC compared with men with BMI 23 to 25 kg.m(-2). For women, this increase in risk was 1.7-fold. Change in BMI between age 20 years and baseline was also associated with MCPC in both men and women. In men and women, none of these associations were observed for NMCPC, with the exception of the increased risk for pancreatic cancer in obese men. We observed statistically significant associations between both BMI, gain in BMI, and pancreatic cancer risk. These associations are observed only in MCPC and not in NMCPC. If MCPC and NMCPC had been considered as one group, the reported associations would not have been detected. These findings stress the need to evaluate heterogeneity among pancreatic cancer cases in etiologic studies.